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Galactokinase Deficiency

  • Author: Karl S Roth, MD; Chief Editor: Maria Descartes, MD  more...
 
Updated: Sep 08, 2015
 

Background

As with all hexose sugars, metabolism of ingested galactose requires an initial phosphorylation of the molecule using adenosine triphosphate (ATP). Unlike the metabolism of glucose, which ordinarily depends on the activity of hexokinase with a wide substrate-specificity to carry out this reaction, substrate-specific galactokinase activity exclusively phosphorylates galactose.[1]

In 1965, galactokinase deficiency was first identified in a patient who presented with cataracts and galactosuria that developed upon drinking milk. The concurrence of cataracts and galactosuria in a single individual suggested the possibility of a new type of galactosemia. This presentation differed from that of classic galactosemia in many important aspects; neither hepatosplenomegaly nor signs of mental retardation were present. When the researchers realized that the patient did not accumulate galactose-1-phosphate despite the accumulated galactose, the patient's underlying defect was deduced as the lack of the enzyme mediating 1-phosphorylation of galactose.

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Pathophysiology

See the image below.

UDP-galactose synthesis and galactosemia. The most UDP-galactose synthesis and galactosemia. The most common form of galactosemia is due to a deficiency of galactose-1-phosphate uridyltransferase (GALT). This enzyme normally uses galactose-1-phosphate derived from dietary galactose. In the absence of GALT, galactose-1-phosphate accumulates, along with excessive galactose and its oxidative and reductive products galactitol and galactonate (not shown). UDP-galactose synthesis may also be impaired in the absence of GALT but not completely because UDP-galactose-4′-epimerase (GALE) can form UDP-galactose from UDP-glucose and can supply the donor to galactosyltransferases required for normal glycoconjugate biosynthesis.

An appreciation of the differences between the enzyme deficiencies and their clinical manifestations is key to understanding the pathophysiology of galactokinase and galactose-1-phosphate uridyltransferase galactosemias. Whereas vomiting, failure to thrive, jaundice, hepatomegaly, and cataracts are characteristic of the onset of transferase-deficient galactosemia, cataract development is usually the only symptom observed in an infant with kinase deficiency. In people with transferase-deficient galactosemia, galactose-1-phosphate accumulates; in those with kinase deficiency, galactose-1-phosphate cannot be produced. Galactose-1-phosphate is assumed to be the substance that causes the devastating manifestations seen in people with classic galactosemia. Note that this assumption lacks definitive proof despite the intrinsic and compelling logic.

In contrast, the mechanism that produces galactose-related cataracts is understood fairly well. The lens of the eye contains the aldose reductase enzyme. When presented with accumulated galactose, this enzyme reduces the aldehydic end group and produces galactitol, the analogous sugar alcohol. This compound exerts osmotic pressure within the lens because it slowly diffuses. While the induced lenticular swelling is not solely responsible for subsequent cataract formation, most researchers believe that the inciting event is galactitol rather than galactose-1-phosphate accumulation. The evidence favors this view because patients with galactokinase deficiency who cannot produce galactose-1-phosphate still form cataracts.[2]

While patients who are deficient in galactokinase accumulate galactitol in the liver at rates comparable to those with transferase-deficient galactosemia, only the latter display evidence of hepatic damage. Hence, much remains to be learned about the pathophysiologic implications of galactose metabolic impairment.

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Epidemiology

Frequency

United States

Traditionally, most newborn screening programs were designed to identify transferase deficiency; consequently, accumulated galactose in submitted blood samples could be missed.[3] However, with the advent of cost-effective tandem mass spectrometry (MS/MS) newborn screening technology, which has been widely adopted in the United States and the rest of the developed world, screening for galactokinase deficiency is improving.

At present, 17 states in the United States either specifically include MS/MS in their newborn screening, or they use screening technology that is likely to detect galactokinase deficiency.[4] Accordingly, because such screening technology is relatively recent, the data are insufficient to provide an accurate assessment of the prevalence of galactokinase deficiency; however, the estimated range is 1 per 50,000-100,000 live births.

International

The prevalence among certain Eastern European populations, in particular the Romani (Gypsy) population, is estimated to be approximately 1 per 10,000. The Romani people generally possess a mutation known as P28T, considered the founder mutation.

Mortality/Morbidity

The literature indicates no risk of mortality. Morbidity is limited to cataract formation in untreated individuals, although rare cases of pseudotumor cerebri have been reported. Both resolve with effective therapy. Mental retardation and hepatic damage are not associated with galactokinase deficiency.

Sex

As an autosomal recessive condition, the disorder is distributed equally between sexes.

Age

Because galactokinase deficiency is a genetic disease, it is present from conception and may be discovered at birth through the presence of congenital cataracts.

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Contributor Information and Disclosures
Author

Karl S Roth, MD Retired Professor and Chair, Department of Pediatrics, Creighton University School of Medicine

Karl S Roth, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Pediatrics, American College of Nutrition, American Pediatric Society, American Society for Nutrition, American Society of Nephrology, Association of American Medical Colleges, Medical Society of Virginia, New York Academy of Sciences, Sigma Xi, Society for Pediatric Research, Southern Society for Pediatric Research

Disclosure: Nothing to disclose.

Specialty Editor Board

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Eric T Rush, MD, FAAP, FACMG Clinical Geneticist, Munroe-Meyer Institute for Genetics and Rehabilitation; Assistant Professor of Pediatrics and Internal Medicine, University of Nebraska Medical Center

Eric T Rush, MD, FAAP, FACMG is a member of the following medical societies: American Academy of Pediatrics, American College of Medical Genetics and Genomics, American College of Physicians, Nebraska Medical Association

Disclosure: Serve(d) as a speaker or a member of a speakers bureau for: Alexion Pharmaceuticals<br/>Honoraria for: Alexion Pharmaceuticals and Biomarin Pharmaceuticals.

Chief Editor

Maria Descartes, MD Professor, Department of Human Genetics and Department of Pediatrics, University of Alabama at Birmingham School of Medicine

Maria Descartes, MD is a member of the following medical societies: American Academy of Pediatrics, American College of Medical Genetics and Genomics, American Medical Association, American Society of Human Genetics, Society for Inherited Metabolic Disorders, International Skeletal Dysplasia Society, Southeastern Regional Genetics Group

Disclosure: Nothing to disclose.

Additional Contributors

Michael Fasullo, PhD Senior Scientist, Ordway Research Institute; Associate Professor, State University of New York at Albany; Adjunct Associate Professor, Center for Immunology and Microbial Disease, Albany Medical College

Michael Fasullo, PhD is a member of the following medical societies: Radiation Research Society, American Society for Biochemistry and Molecular Biology, Genetics Society of America, Environmental Mutagenesis and Genomics Society

Disclosure: Nothing to disclose.

References
  1. Cuthbert C, Klapper H, Elsas L. Diagnosis of inherited disorders of galactose metabolism. Curr Protoc Hum Genet. 2008 Jan. Chapter 17:Unit 17.5. [Medline].

  2. Janzen N, Illsinger S, Meyer U, Shin YS, Sander J, Lücke T, et al. Early cataract formation due to galactokinase deficiency: impact of newborn screening. Arch Med Res. 2011 Oct. 42(7):608-12. [Medline].

  3. Hennermann JB, Schadewaldt P, Vetter B, Shin YS, Mönch E, Klein J. Features and outcome of galactokinase deficiency in children diagnosed by newborn screening. J Inherit Metab Dis. 2011 Apr. 34(2):399-407. [Medline].

  4. The University of Texas Health Science Center at San Antonio. National newborn screening status report. Updated 01/06/13. Available at http://genes-r-us.uthscsa.edu/sites/genes-r-us/files/nbsdisorders.pdf. Accessed: April 14, 2014.

  5. Kalaydjieva L, Perez-Lezaun A, Angelicheva D, et al. A founder mutation in the GK1 gene is responsible for galactokinase deficiency in Roma (Gypsies). Am J Hum Genet. 1999 Nov. 65(5):1299-307. [Medline]. [Full Text].

  6. Park HD, Kim YK, Park KU, Kim JQ, Song YH, Song J. A novel c.-22T>C mutation in GALK1 promoter is associated with elevated galactokinase phenotype. BMC Med Genet. 2009 Mar 24. 10:29. [Medline]. [Full Text].

  7. Park HD, Bang YL, Park KU, Kim JQ, Jeong BH, Kim YS, et al. Molecular and biochemical characterization of the GALK1 gene in Korean patients with galactokinase deficiency. Mol Genet Metab. 2007 Jul. 91(3):234-8. [Medline].

  8. Berry GT. The role of polyols in the pathophysiology of hypergalactosemia. Eur J Pediatr. 1995. 154(7 Suppl 2):S53-64. [Medline].

  9. Beutler E, Matsumoto F, Kuhl W, Krill A, Levy N, Sparkes R, et al. Galactokinase deficiency as a cause of cataracts. N Engl J Med. 1973 Jun 7. 288(23):1203-6. [Medline].

  10. Bosch AM, Bakker HD, van Gennip AH, van Kempen JV, Wanders RJ, Wijburg FA. Clinical features of galactokinase deficiency: a review of the literature. J Inherit Metab Dis. 2002 Dec. 25(8):629-34. [Medline].

  11. Gitzelmann R. Hereditary galactokinase deficiency, a newly recognized cause of juvenile cataracts. Pediatr Res. 1967. 1:14-23.

  12. Hunter M, Heyer E, Austerlitz F. The P28T mutation in the GALK1 gene accounts for galactokinase deficiency in Roma(Gypsy) patients across Europe. Pediatr Res. 2002. 51:602-606.

  13. Kerr MM, Logan RW, Cant JS, Hutchison JH. Galactokinase deficiency in a newborn infant. Arch Dis Child. 1971 Dec. 46(250):864-6. [Medline].

  14. Levy NS, Krill AE, Beutler E. Galactokinase deficiency and cataracts. Am J Ophthalmol. 1972 Jul. 74(1):41-8. [Medline].

  15. Pickering WR, Howell RR. Galactokinase deficiency: clinical and biochemical findings in a new kindred. J Pediatr. 1972 Jul. 81(1):50-5. [Medline].

  16. Reich S, Hennerman J, Vetter B. An unexpectedly high frequency of hypergalactosemia in an immigrant Bosnian population revealed by newborn screening. Pediatr Res. 2002. 51:598-601.

  17. Sangiuolo F, Magnani M, Stambolian D. Biochemical characterization of two GALK1 mutations in patients with galactokinase deficiency. Hum Mutat. 2004. 23:396.

  18. Thalhammer O, Gitzelmann R, Pantlitschko M. Hypergalactosemia and galactosuria due to galactokinase deficiency in a newborn. Pediatrics. 1968 Sep. 42(3):441-5. [Medline].

 
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UDP-galactose synthesis and galactosemia. The most common form of galactosemia is due to a deficiency of galactose-1-phosphate uridyltransferase (GALT). This enzyme normally uses galactose-1-phosphate derived from dietary galactose. In the absence of GALT, galactose-1-phosphate accumulates, along with excessive galactose and its oxidative and reductive products galactitol and galactonate (not shown). UDP-galactose synthesis may also be impaired in the absence of GALT but not completely because UDP-galactose-4′-epimerase (GALE) can form UDP-galactose from UDP-glucose and can supply the donor to galactosyltransferases required for normal glycoconjugate biosynthesis.
 
 
 
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